• Chronic inflammation is prolonged inflammation lasting weeks to months.
• In chronic inflammation, inflammation + tissue injury + attempts at repair occur together in different proportions.
• It may develop after acute inflammation or may start slowly as a smoldering, progressive process without a previous acute phase.
• Chronic inflammation can cause marked tissue damage and scarring, sometimes with relatively few inflammatory cells.
• Hepatic cirrhosis is an example in which extensive tissue damage and fibrosis may occur.

Causes of Chronic Inflammation

• Persistent infections: Chronic inflammation occurs when microorganisms are difficult to eliminate, such as mycobacteria, certain viruses, fungi, and parasites.
• Sometimes incompletely resolved acute inflammation → progresses to chronic inflammation.
• Example: acute bacterial lung infection → chronic lung abscess.
• Hypersensitivity diseases: Excessive or inappropriate activation of the immune system can cause persistent inflammation.
• In autoimmune diseases, the immune system reacts against self-antigens → continuous immune reaction → chronic tissue damage and inflammation.
• Examples include rheumatoid arthritis and multiple sclerosis.
• In allergic diseases, excessive immune responses against common environmental substances → chronic inflammation.
• Example: bronchial asthma.
• Repeated attacks may produce a mixture of acute and chronic inflammation, while fibrosis may dominate in late stages.
• Prolonged exposure to toxic agents: Chronic inflammation can occur after long exposure to harmful substances from outside or inside the body.
• Exogenous example: Long-term inhalation of nondegradable silica particles → chronic lung inflammation → silicosis.
• Endogenous example: Excessive production and deposition of cholesterol and other lipids in arterial walls → chronic inflammation → atherosclerosis.
• Chronic inflammation may also contribute to diseases not traditionally considered inflammatory.
• Examples include Alzheimer disease, metabolic syndrome, and associated type 2 diabetes.

KEY CONCEPT

• Chronic inflammation = prolonged inflammation + tissue injury + repair occurring together.
• Persistent infection → chronic inflammation.
• Autoimmunity/allergy → repeated immune activation → chronic inflammation.
• Long-term toxic exposure → chronic tissue injury and inflammation.
• Late chronic inflammation may lead to fibrosis and scarring.

Conceptual Examples

• Tuberculosis: Persistent mycobacteria cannot be easily eliminated → prolonged immune response → chronic inflammation.
• Rheumatoid arthritis: Immune system attacks self-antigens → repeated tissue injury → chronic inflammation.
• Silicosis: Long-term inhaled silica remains in lung tissue → persistent inflammation → lung fibrosis.
• Atherosclerosis: Cholesterol and lipids accumulate in arterial walls → persistent inflammation → chronic arterial damage.

Morphologic Features

• Acute inflammation mainly shows vascular changes + edema + neutrophil infiltration.
• In contrast, chronic inflammation has three major morphologic features:
  • Mononuclear cell infiltration: mainly macrophages, lymphocytes, and plasma cells (Fig. 2.14).
  • Tissue destruction: caused by the persistent harmful agent or by the inflammatory cells themselves.
  • Attempts at healing: damaged tissue is replaced by connective tissue.
• Healing occurs through:
  • Angiogenesis → formation/proliferation of small blood vessels.
  • Fibrosis → formation of fibrous connective tissue.
  • Eventually → scar formation.
• Angiogenesis and fibrosis are important parts of tissue repair.

Cells and Mediators of Chronic Inflammation

• Chronic inflammation is characterized by a combination of leukocyte infiltration + tissue damage + fibrosis.
• These changes result from local activation of different cell types and production of inflammatory mediators.

Role of Macrophages

• Macrophages are the dominant cells in most chronic inflammatory reactions.
• Their major actions include:
  • Destroying foreign agents and damaged tissues
  • Producing cytokines and growth factors
  • Activating other cells, especially T lymphocytes
• Macrophages are professional phagocytes → their main function is to ingest and destroy microbes, particulate material, and dead cells.
• They also have important roles in host defense, inflammation, and tissue repair.
• Macrophages are normally scattered throughout most connective tissues.
• Their circulating form in blood is called a monocyte.
• Specialized tissue macrophages include:
  • Liver → Kupffer cells
  • Spleen and lymph nodes → sinus histiocytes
  • Central nervous system → microglial cells
  • Lungs → alveolar macrophages
• Together, circulating monocytes and tissue macrophages form the mononuclear phagocyte system.
• Blood monocytes are about 10–15 μm in diameter and have a bean-shaped nucleus + finely granular cytoplasm (Fig. 2.15).
• Tissue macrophages contain abundant cytoplasm, many phagocytic vacuoles containing ingested material, and numerous lysosomes and other organelles.

KEY CONCEPT

• Chronic inflammation = mononuclear cells + tissue destruction + attempts at repair/fibrosis.
• Macrophages are the major cells of chronic inflammation.
• Monocyte in blood → macrophage in tissue.
• Macrophages → phagocytosis + cytokine/growth factor secretion + T-cell activation → inflammation and repair.

Conceptual Examples

• Persistent tissue injury: Harmful agent remains → macrophages and lymphocytes accumulate → tissue damage continues → fibrosis and scar formation.
• Liver: Tissue-resident macrophage → Kupffer cell.
• Brain: Tissue-resident macrophage → microglial cell.
• Lung: Tissue-resident macrophage → alveolar macrophage.

Role of Macrophages

• Tissue macrophages come from two main developmental sources:
  • Bone marrow hematopoietic stem cells
  • Embryonic yolk sac and fetal liver progenitors (Fig. 2.16)
• During inflammation → bone marrow progenitors produce monocytes → monocytes enter blood → migrate into tissues → become macrophages.
• Monocytes enter tissues using mechanisms similar to neutrophils, especially adhesion molecules and chemokines.
• Macrophages survive longer in tissues than many other leukocytes.
• Therefore, within about 48 hours after inflammation begins, macrophages often become the dominant inflammatory cells.
• Tissue-resident macrophages, such as microglia and Kupffer cells, mainly originate from the yolk sac or fetal liver during embryonic development.
• These cells enter tissues early → remain there for long periods → are maintained mainly by local proliferation of resident macrophages.
• Macrophages can be activated through two major pathways: classical and alternative activation (Fig. 2.17).
• The pathway followed depends on the type of activating signal.
• Classical macrophage activation (M1): triggered by microbial products such as endotoxin acting through TLRs and other sensors, and by IFN-γ produced during immune responses.
• M1 macrophages produce NO + ROS and increase lysosomal enzymes → stronger killing of ingested microorganisms.
• M1 macrophages also secrete cytokines that promote inflammation.
• Therefore, M1 macrophages mainly function in microbial killing and promotion of inflammation.
• They are important for eliminating infections but can also damage normal tissues.
• Alternative macrophage activation (M2): mainly stimulated by IL-4 and IL-13 produced by T lymphocytes and other cells.
• M2 macrophages are not strongly microbicidal.
• Their main role is tissue repair and control of inflammation.
• M2 macrophages release growth factors → promote angiogenesis + fibroblast activation + collagen synthesis.
• They also help suppress inflammation.
• A useful concept is:
  • M1 first → destroy harmful agent and promote inflammation
  • M2 later → reduce inflammation and promote tissue repair
• However, this exact sequence is not clearly established in all inflammatory reactions.
• In reality, macrophages do not exist only as pure M1 or M2 forms; many intermediate macrophage populations also exist.

KEY CONCEPT

• Bone marrow → monocyte → blood → tissue → macrophage.
• M1 macrophage → IFN-γ/microbial products → NO + ROS + lysosomal enzymes → microbial killing + inflammation.
• M2 macrophage → IL-4 + IL-13 → angiogenesis + fibroblast activation + collagen → tissue repair.
• M1 = Kill and Inflame.
• M2 = Mend and Repair.

Conceptual Examples

• Bacterial infection: Microbial products + IFN-γ → M1 activation → ROS/NO produced → microbes killed → inflammation increases.
• Healing tissue: IL-4 and IL-13 → M2 activation → fibroblasts and blood vessel growth stimulated → collagen deposition and repair.
• Persistent inflammation: Monocytes continue entering tissue → become long-lived macrophages → macrophages become the dominant cells after about 48 hours.

Fig. 2.16 — Maturation of Mononuclear Phagocytes (Macrophages)

This figure answers one basic question:

Where do macrophages come from?

There are 2 main routes:

Route A — After birth / during inflammation

Bone marrow → hematopoietic stem cell → blood monocyte → tissue macrophage

Route B — During embryonic development

Yolk sac / fetal liver precursor → tissue-resident macrophage

The most important difference is:

Route A passes through a blood monocyte.
Route B establishes long-lived macrophages in tissues early in life.

First: What does “mononuclear phagocyte” mean?

Break the words:

• Mono = one
• Nuclear = nucleus
• Phagocyte = cell that eats

So a mononuclear phagocyte is an immune cell with one main nucleus that can engulf microbes and dead material.

The important cells here are:

Monocytes → Macrophages

What is a macrophage?

A macrophage is a large immune cell mainly found in tissues.

Main jobs

Macrophage
→ eats microbes
→ eats dead cells/debris
→ releases cytokines
→ presents antigens to T cells
→ helps inflammation
→ helps tissue repair

Easy memory

MACRO = big
PHAGE = eater

So:

Macrophage = big eater

PANEL A — BLUE AREA

Derived from hematopoietic precursors (postnatal)

Postnatal = after birth.

This upper pathway is particularly important during inflammatory reactions.

STEP 1 — Bone marrow

The first picture on the left is:

Bone marrow

Bone marrow is the major site where blood cells are produced after birth.

The caption underneath says:

Site of blood cell formation

So the first yellow arrow means:

Bone marrow → blood-cell precursor

STEP 2 — Hematopoietic stem cell (HSC)

The orange round cell is:

Hematopoietic stem cell

Hematopoietic = blood-forming.

A hematopoietic stem cell is a parent cell capable of giving rise to all major blood-cell lineages.

For this figure, we follow only one pathway:

HSC → monocyte lineage

The figure calls it a self-renewing precursor cell.

Self-renewing means

The stem-cell population can maintain itself by making new stem cells while also producing cells that mature into blood cells.

So:

HSC
→ maintains its own population
AND
→ produces blood-cell precursors

Yellow arrow: HSC → Blood monocyte

The next yellow arrow means:

Hematopoietic stem cell
→ passes through intermediate precursor stages
→ produces a monocyte

Those intermediate stages are simply not shown.

The figure is giving you the simplified pathway.

STEP 3 — Blood monocyte

Now look at the pink/red blood vessel.

Inside it is a round orange cell labeled:

Blood monocyte

A monocyte is a white blood cell that circulates in blood.

The text underneath says:

Circulates in blood

Very easy concept

Think:

Monocyte = traveling form

It travels through the bloodstream until inflammatory signals tell it to leave.

What is the pink tube?

The pink tube represents a:

Blood vessel

• Pink lining = endothelial cells
• Orange round cell inside = monocyte
• Yellow arrow = direction of maturation/movement

STEP 4 — Monocyte leaves blood

The next yellow arrow points from:

Blood monocyte → Macrophage

During inflammation, chemokines and adhesion molecules help the monocyte:

stick to vessel wall
→ cross the endothelium
→ enter tissue

This movement out of the blood is called:

Emigration / extravasation

Very simply:

Monocyte leaves the bloodstream and enters the tissue.

STEP 5 — Monocyte becomes macrophage

Once inside tissue:

Monocyte → differentiates → macrophage

What does “differentiate” mean?

Differentiate = change into a more specialized mature cell.

So:

Blood monocyte
→ enters tissue
→ becomes larger and more specialized
→ macrophage

The irregular orange cell represents the macrophage.

Why does the macrophage look irregular?

The monocyte is shown as a fairly smooth round cell.

The macrophage has:

• more cytoplasm
• irregular edges
• more cellular machinery

because it is now specialized for:

phagocytosis + secretion + tissue defense

The yellow arrow now SPLITS

After the macrophage, the yellow arrow divides upward and downward.

This means:

Macrophages can enter and function in different tissues.

The right upper box shows:

Activated macrophages in inflammation

Examples shown:

• macrophages in skin
• macrophages in intestinal tract

What is an “activated macrophage”?

A macrophage may already be present, but during infection or tissue damage it receives activating signals.

Examples of activating signals include:

• microbial products
• inflammatory cytokines
• signals from T cells

Then:

Macrophage → activated macrophage

An activated macrophage becomes much more effective.

What does an activated macrophage do?

1. Phagocytosis

It eats:

• bacteria
• dead cells
• damaged tissue

2. Killing

It produces substances that help destroy microbes.

3. Cytokine secretion

It can release cytokines such as:

• TNF
• IL-1
• chemokines

These recruit and activate more inflammatory cells.

4. Repair

It can also release growth factors that promote healing.

So:

Activated macrophage
→ kill + clean + signal + repairComplete PANEL A pathway

Follow every yellow arrow:

Bone marrow

→ hematopoietic stem cell

→ blood monocyte

→ monocyte circulates in blood

→ monocyte enters tissue

→ macrophage

→ becomes activated during inflammation

→ participates in inflammatory defense

PANEL B — PINK AREA

Derived from embryonic precursors

Now we have a different origin.

This pathway begins during:

Early embryonic development

Look at the lower-left embryo.

Two important structures are labeled:

• Yolk sac
• Liver

Here, “liver” means the fetal liver.

STEP 1 — Yolk sac and fetal liver

Very early in development, the bone marrow is not yet functioning as the main adult blood-forming organ.

Early blood and immune-cell precursors arise in places such as:

Yolk sac

and later:

Fetal liver

These can produce macrophage precursors.

Yellow arrow → progenitor

The yellow arrow moves from the embryo toward:

Progenitor in yolk sac or fetal liver

What is a progenitor?

A progenitor cell is an immature cell that is already moving toward a specific cell lineage.

Very simply:

Stem cell
= many possible futures

Progenitor
= fewer choices; already committed toward a certain family

Here:

Embryonic progenitor
→ macrophage lineage

Important label:

“Populates tissues early in development”

This is the key concept.

These embryonic macrophage precursors move into organs while the fetus is developing.

So:

Embryonic precursor
→ migrates into developing tissue
→ becomes resident macrophage

Notice the VERY LONG yellow arrow

This long yellow arrow is important.

It goes:

Embryonic progenitor → Tissue-resident macrophage

Notice something missing:

There is NO blood monocyte stage shown.

That is intentional.

This teaches:

Not every macrophage has to arise from an adult blood monocyte.

Many long-lived tissue-resident macrophages were seeded into organs during embryonic development.

STEP 2 — Tissue-resident macrophage

The irregular orange cell is labeled:

Tissue-resident macrophage

Tissue-resident means:

A macrophage that normally lives permanently in a particular tissue.

The caption says:

Long-lived in tissue (self-maintained)What does “self-maintained” mean?

Many resident macrophage populations can maintain themselves locally.

That means:

existing resident macrophage
→ divides
→ produces more resident macrophages

They may not need constant replacement from circulating monocytes under normal conditions.

This is called:

Self-renewal / local proliferation

The yellow arrow again splits

The tissue-resident macrophage gives examples in different organs.

The figure shows three classic examples:

1. Kupffer cells — Liver

The liver is shown in the upper-left of the right box.

Its resident macrophages are called:

Kupffer cells

They help:

• remove microbes from blood
• remove cellular debris
• process material coming from the intestine
• participate in liver inflammation

Exam memory

Kupffer = Liver. Microglia — Brain

The brain is shown below.

Its specialized resident macrophage population is:

Microglia

They:

• monitor the central nervous system
• remove dead cells
• respond to infection/injury
• participate in neuroinflammation

Exam memory

Microglia = Brain

3. Alveolar macrophages — Lung

The lung is shown on the right.

These are:

Alveolar macrophages

They live around the alveoli.

Alveoli

= tiny air sacs where gas exchange occurs.

Alveolar macrophages:

• eat inhaled particles
• remove microorganisms
• clean cellular debris

Exam memory

Alveolar macrophage = Lung

NOW COMPARE PANEL A WITH PANEL B

This is the most important part of the entire figure.

Panel A	Panel B
Postnatal route	Embryonic route
Begins in bone marrow	Begins in yolk sac/fetal liver
Hematopoietic precursor	Embryonic progenitor
Goes through blood monocyte	No blood-monocyte stage shown
Monocyte enters tissue	Cells populate tissues during development
Important during inflammation	Creates many long-lived resident populations
Recruited macrophages increase during inflammation	Often maintained locally

KEY POINT A — Postnatal origin

The bottom box summarizes:

Bone marrow HSC

→ monocytes produced

Monocytes

→ circulate in blood

Monocytes

→ enter tissue

In tissue

→ become macrophages

So memorize:

Bone → Blood → Tissue

Bone marrow
→ monocyte in blood
→ macrophage in tissueKEY POINT B — Embryonic origin

Yolk sac / fetal liver

→ embryonic precursor

Precursor

→ enters tissues early in development

Tissue macrophage

→ remains long-lived

Resident population

→ may maintain itself by local proliferation

So:

Embryo → organ early → resident for long time

KEY POINT C — Two types emphasized in the figure

Monocyte-derived macrophages

These arise from:

blood monocytes

They increase greatly during inflammation.

Many recruited macrophages are relatively shorter-lived compared with long-lived resident populations.

Tissue-resident macrophages

These are established in particular tissues.

Many are:

• long-lived
• locally maintained
• specialized for their organ

Examples:

Liver → Kupffer cells

Brain → Microglia

Lung → Alveolar macrophages

KEY POINT D — Functions of macrophages

The bottom-right box gives 3 major functions.

1. Phagocytosis

Phagocytosis = engulfing and digesting material.

Macrophages eat:

pathogens + dead cells + debris

2. Antigen presentation

After eating a microbe:

Macrophage digests microbe
→ takes microbial antigen
→ displays it on its surface
→ presents it to T cells

So macrophages help connect:

innate immunity → adaptive immunity

3. Secretion of cytokines and growth factors

Cytokines

help regulate inflammation.

For example:

TNF / IL-1 / chemokines
→ recruit and activate inflammatory cells

Growth factors

help tissue repair.

So macrophages can participate in both:

Inflammation AND healing

What Do the COLORS Mean?

These are teaching colors, not the actual colors of the cells inside the body.

Light blue upper background

= postnatal / bone-marrow route

Light pink lower background

= embryonic route

Yellow arrows

= direction of development, migration, or differentiation

Orange round cells

= cells of the monocyte/macrophage lineage

Pink-red tube

= blood vessel

Irregular orange cell

= macrophage

Blue headings

= adult/postnatal pathway and labels

Purple/magenta heading

= embryonic pathway

Beige bottom box

= summary/key exam points

One Important Concept Students Often Mix Up

Do not memorize:

❌ “Every tissue macrophage comes from a blood monocyte.”

That is too simple and not completely correct.

Instead remember:

During inflammation

Bone marrow
→ monocytes
→ blood
→ tissue
→ macrophages

But many long-lived resident macrophages originate from:

Yolk sac/fetal liver
→ tissue during embryonic development
→ resident macrophage

Whole Figure in One Simple Story

ROUTE A — After birth

Bone marrow

↓
Hematopoietic stem cell

↓
Monocyte produced

↓
Monocyte enters blood

↓
Travels in circulation

↓
Inflammation occurs

↓
Monocyte leaves blood

↓
Enters tissue

↓
Becomes macrophage

↓
Macrophage becomes activated

↓
Kills microbes + removes debris + releases cytokines

ROUTE B — Before birth

Yolk sac / fetal liver

↓

Embryonic progenitor

↓

Moves into developing organs

↓

Becomes tissue-resident macrophage

↓

Lives there for a long time

↓

Often maintains itself locally

↓

Examples:

Liver → Kupffer cells
Brain → Microglia
Lung → Alveolar macrophages

⭐ Easiest Memory Trick

MONO = Moving in blood

MACRO = Moved into tissue

So:

Monocyte in BLOOD → Macrophage in TISSUE

For resident macrophages remember:

K-M-A

Kupffer → liver
Microglia → brain
Alveolar macrophage → lung

Key Exam Points

• Monocytes circulate in blood; macrophages mainly live in tissues.
• During inflammatory reactions, many macrophages are recruited from bone-marrow-derived monocytes.
• Monocyte enters tissue → differentiates into macrophage.
• Many long-lived tissue-resident macrophages originate from embryonic yolk sac/fetal liver precursors.
• Resident macrophages may be maintained by local self-renewal.
• Kupffer cells = liver.
• Microglia = brain.
• Alveolar macrophages = lung.
• Macrophages perform phagocytosis, antigen presentation, cytokine secretion, and tissue repair.

2-Line Exam Recall

Bone marrow → HSC → blood monocyte → tissue macrophage, especially during inflammation.

Yolk sac/fetal liver → embryonic precursor → long-lived tissue-resident macrophages such as Kupffer cells, microglia, and alveolar macrophages.

Fig. 2.17 — Classical (M1) vs Alternative (M2) Macrophage Activation

This figure is showing one very important idea:

The same macrophage can behave in two different ways depending on the signal it receives.

Think of a macrophage as having 2 major modes:

• M1 = FIGHT mode → kills microbes and increases inflammation
• M2 = FIX mode → reduces inflammation and repairs tissue

First: Start from the center

The orange cell in the middle is a:

Macrophage

At first, think of it as a macrophage waiting for instructions.

It can receive different chemical signals.

If it receives:

Microbial TLR ligands + IFN-γ

→ it becomes M1

If it receives:

IL-4 + IL-13

→ it becomes M2

So the entire figure begins with:

Macrophage

↙️ different signal different signal ↘️

M1 M2T SIDE — M1 Macrophage

The heading says:

Classically Activated Macrophage (M1)

“Classically activated” means:

A macrophage activated mainly to fight microbes and produce inflammation.

Arrow 1: Microbial TLR ligands → M1

Look at the yellow arrow pointing from the center toward the left.

Above it:

Microbial TLR-ligands, IFN-γ

These are the signals that push the macrophage toward M1 activation.hat is a TLR?

TLR = Toll-Like Receptor

TLRs are receptors present on innate immune cells such as macrophages.

Their job is to recognize common microbial molecules.

Examples:

• bacterial LPS
• bacterial cell-wall molecules
• viral nucleic acids

A microbial molecule that binds a TLR is called a:

TLR ligand

So:

Microbial molecule binds TLR on macrophage
→ macrophage detects infection
→ M1 activation

What is IFN-γ?

IFN-γ = Interferon-gamma

It is a powerful macrophage-activating cytokine.

It is produced mainly by:

• Th1 cells
• NK cells

Its message to macrophages is basically:

“Become better at killing microbes.”

So:

Microbial TLR signal + IFN-γ
→ strong classical macrophage activation
→ M1 macrophage

Why are BOTH shown together?

Because the strongest microbicidal macrophage activation occurs when it receives:

Microbial signal
+
IFN-γ

So one signal says:

“There is a microbe.”

The other says:

“Attack strongly.”

M1 now follows TWO important branches

Look at the M1 macrophage.

One yellow arrow goes downward.

Another curved yellow arrow goes toward inflammatory cytokines.

These represent two major M1 functions.

M1 Function 1 — Kill microbes

The downward arrow leads to:

ROS, NO, lysosomal enzymes

Let’s define each.

ROS

ROS = Reactive Oxygen Species

These are highly reactive oxygen-containing chemicals.

Examples include:

• superoxide
• hydrogen peroxide

They damage and kill microbes.

Very simply:

M1 macrophage → ROS → microbial damage

NO

NO = Nitric Oxide

Macrophages can produce nitric oxide using inducible nitric oxide synthase.

NO is toxic to many microbes.

So:

M1 → NO → microbial killing

Lysosomal enzymes

Macrophages contain lysosomes.

Lysosomes contain powerful digestive enzymes.

After a macrophage eats a bacterium:

Bacterium enters macrophage
→ joins lysosome
→ lysosomal enzymes digest it

Downward arrow → Microbicidal actions

The purple box says:

Microbicidal actions:

phagocytosis and killing of bacteria and fungi

Microbicidal means:

microbe-killing

So the sequence is:

M1 macrophage
→ ROS + NO + lysosomal enzymes
→ phagocytosis
→ bacterial/fungal killing

What is phagocytosis?

Phagocytosis = eating a particle or microbe

Sequence:

Macrophage recognizes microbe
→ surrounds it
→ takes it inside
→ lysosomes fuse
→ microbe is destroyed

Easy memory

M1 = Murder microbes

M1 Function 2 — Produce inflammatory cytokines

Now look at the curved yellow arrow from M1.

It leads to:

• IL-1
• TNF
• IL-12
• IL-6
• chemokines

These are inflammatory mediators produced by M1 macrophages.

IL-1 and TNF

These are major inflammatory cytokines.

They cause:

• endothelial activation
• leukocyte recruitment
• fever
• increased inflammatory responses

So:

M1 → IL-1 + TNF → inflammation ↑

IL-6

IL-6 has several systemic inflammatory effects.

A major one is:

IL-6 → liver → acute-phase proteins

For example:

CRP increases

IL-12

IL-12 helps activate:

• NK cells
• T cells

and promotes:

IFN-γ production

This can further activate macrophages.

So you can get a reinforcing loop:

M1 → IL-12 → IFN-γ ↑ → stronger macrophage activation

Chemokines

Chemokines = cytokines that attract leukocytes

Think:

Chemokines = chemical GPS signals

They tell neutrophils and other leukocytes:

“Come to this infected area.”

So:

M1 → chemokines → leukocyte recruitment → inflammation ↑

Green PLUS sign

Look at the green + before the arrow toward inflammation.

This means:

M1 promotes inflammation

So:

M1 cytokines
→ increase inflammation

That is why the green plus sign is shown.

LEFT SIDE COMPLETE PATH

Signal

Microbial TLR ligands + IFN-γ

↓

M1 macrophage

Then two major actions:

Action 1

ROS + NO + lysosomal enzymes
→ phagocytosis
→ killing bacteria and fungi

Action 2

IL-1 + TNF + IL-12 + IL-6 + chemokines
→ inflammation ↑

RIGHT SIDE — M2 Macrophage

Now look at the blue-shaded box on the right.

The heading says:

Alternatively Activated Macrophage (M2)

This macrophage has a different job.

Instead of mainly fighting microbes, M2 mainly helps:

• suppress inflammation
• repair tissue
• promote wound healing
• produce fibrosis

Arrow: IL-4 + IL-13 → M2

The yellow arrow from the central macrophage points to the right.

Above it:

IL-13
IL-4

These cytokines push the macrophage toward the M2 pathway.

So:

IL-4 + IL-13
→ alternative macrophage activation
→ M2

What are IL-4 and IL-13?

They are cytokines strongly associated with type 2 immune responses.

They can be produced by cells such as:

• Th2 cells
• mast cells
• innate lymphoid cells

Their general message is more like:

M2 → IL-10 and TGF-β

Look at the yellow downward arrow.

The M2 macrophage produces mediators including:

IL-10

IL-10 is strongly:

Anti-inflammatory

It suppresses excessive inflammatory responses.

So:

M2 → IL-10 → inflammation ↓TGF-β

TGF-β = Transforming Growth Factor-beta

It is important in:

• tissue repair
• fibroblast activation
• collagen production
• fibrosis

So:

M2 → TGF-β
→ fibroblasts activated
→ collagen deposited
→ tissue repair / fibrosis

Green box: Anti-inflammatory effects, wound repair, fibrosis

This is the main result of M2 activation.

1. Anti-inflammatory effects

M2 tries to stop excessive inflammatory damage.

Especially through:

IL-10 and TGF-β

2. Wound repair

M2 macrophages produce substances that help repair damaged tissue.

They help:

• fibroblasts
• blood vessel formation
• extracellular matrix production

So:

M2 → repair mechanisms → healing

3. Fibrosis

Fibrosis = excessive collagen/connective tissue deposition

This may be useful during wound healing.

But if too much occurs:

too much collagen → scar formation → fibrosis

So M2 is beneficial for healing, but excessive M2-type repair may contribute to pathological fibrosis.

Red inhibitory line with MINUS sign

This is extremely important.

Look at the red line coming from the M2 side toward Inflammation.

There is a white circle containing:

−

That minus sign means:

M2 inhibits inflammation

So:

M2 → IL-10 / TGF-β → inflammation ↓

Compare:

M1

green +
→ inflammation ↑

M2

red −
→ inflammation ↓

This is the central contrast of the figure.Why Does the Body Need BOTH?

Because inflammation has two phases.

Imagine bacteria enter through a wound.

Early phase

The body needs:

M1

because:

Microbes present → kill them → strong inflammation

But after the microbes have been controlled, continued strong inflammation would damage normal tissue.

Then the body needs:

M2

to say:

“The fight is finishing. Reduce inflammation and repair the damage.”

So ideally:

M1 fights → M2 fixes

Simple Real-Life Story

Imagine your skin becomes infected.

Step 1

Bacteria enter.

↓

Step 2

Microbial products activate TLRs.

↓

Step 3

IFN-γ also activates macrophages.

↓

Step 4

Macrophage becomes M1.

↓

Step 5

M1 produces:

ROS + NO + enzymes

↓

Step 6

Bacteria are killed.

At the same time:

M1 → IL-1/TNF/chemokines → inflammation ↑

↓

Step 7

After infection is controlled, repair signals increase.

↓

Step 8

IL-4 + IL-13 → M2

↓

Step 9

M2 produces:

IL-10 + TGF-β

↓

Step 10

Inflammation decreases.

↓

Step 11

Wound healing starts.

↓

Step 12

Collagen and connective tissue repair the area.

Understand the COLORS

The colors are mainly diagram teaching colors; these molecules are not literally these colors in the body.

Figure feature	Meaning
Orange cells	Macrophages
Yellow arrows	Direction of activation/effect
White background on left	M1/classical pathway
Light blue background on right	M2/alternative pathway
Green +	Promotes inflammation
Red line + −	Suppresses inflammation
Purple boxes	Major final effects
Black text	Important signals/products

M1 vs M2 — Easy Comparison

M1	M2
Classical activation	Alternative activation
Microbial TLR ligands + IFN-γ	IL-4 + IL-13
Fight microbes	Repair tissue
ROS	IL-10
NO	TGF-β
Lysosomal enzymes	Growth/repair responses
IL-1, TNF, IL-6, IL-12	Anti-inflammatory mediators
Inflammation ↑	Inflammation ↓
Microbial killing	Wound repair
Can cause tissue damage if excessive	Can cause fibrosis if excessive

Very Easy Memory Trick

M1 = 1st job: Fight

Think:

M1 = Microbe killer

• microbial products
• IFN-γ
• ROS
• NO
• inflammatory cytokines

M1:

KILL + INFLAME

M2 = 2nd job: Mend

Think:

M2 = Mend tissue

• IL-4
• IL-13
• IL-10
• TGF-β
• repair
• fibrosis

M2:

CALM + REPAIR

One More Excellent Memory

M1 = FIRE 🔥

It increases inflammation and kills microbes.

M2 = FIX 🛠️

It turns inflammation down and repairs tissue.

So:

M1 FIRES — M2 FIXES

Whole Figure in One Flow

M1 pathway

Microbial TLR ligands + IFN-γ

→ macrophage becomes M1

→ ROS + NO + lysosomal enzymes

→ phagocytosis + killing of bacteria/fungi

AND

→ IL-1 + TNF + IL-12 + IL-6 + chemokines

→ inflammation ↑

M2 pathway

IL-4 + IL-13

→ macrophage becomes M2

→ IL-10 + TGF-β

→ inflammation ↓

→ wound repair

→ fibrosis

Key Exam Points

• M1 = classically activated macrophage
• M1 activated by microbial TLR ligands + IFN-γ
• M1 produces ROS, NO, lysosomal enzymes
• M1 kills bacteria and fungi
• M1 produces IL-1, TNF, IL-6, IL-12 and chemokines
• M1 promotes inflammation
• M2 = alternatively activated macrophage
• M2 activated mainly by IL-4 and IL-13
• M2 produces anti-inflammatory/repair mediators including IL-10 and TGF-β
• M2 reduces inflammation
• M2 promotes wound healing and fibrosis

2-line exam recall

M1: TLR ligands + IFN-γ → ROS/NO + inflammatory cytokines → microbial killing and inflammation.

M2: IL-4 + IL-13 → IL-10/TGF-β → anti-inflammatory effects, tissue repair and fibrosis.

Final memory: M1 = Fight; M2 = Fix.

Role of Macrophages

• Activated macrophages help eliminate microbes and other harmful agents and start tissue repair, but they can also cause much of the tissue injury in chronic inflammation.
• Important functions of macrophages include:
  • Phagocytosis: ingest and remove microbes + dead tissue debris.
  • Inflammation: release mediators such as TNF, IL-1, chemokines, and eicosanoids → initiate and maintain inflammatory reactions.
  • Repair: initiate tissue repair + scar formation + fibrosis.
  • Interaction with T lymphocytes: display antigens to T cells and respond to T-cell signals → creates a feedback loop important in cell-mediated immunity.
• After the harmful agent is removed → macrophages usually die or leave through lymphatics to lymph nodes.
• If inflammation continues → macrophages remain because of continued recruitment of blood monocytes + local macrophage proliferation.

Role of Lymphocytes

• T and B lymphocytes are activated by microbes and other environmental antigens → help amplify and maintain chronic inflammation.
• Lymphocytes mainly function in adaptive immunity, but they are also commonly present in chronic inflammation.
• When lymphocytes remain activated → inflammation tends to become persistent and severe.
• Strong chronic inflammatory reactions, especially granulomatous inflammation, depend heavily on interactions between lymphocytes and macrophages.
• In autoimmune and other hypersensitivity diseases, lymphocytes may become the dominant inflammatory cells.
• CD4+ T lymphocytes release cytokines that determine the type of inflammatory response.
• There are three important CD4+ T-cell subsets:
  • Th1 cells → IFN-γ → classical (M1) macrophage activation.
  • Th2 cells → IL-4 + IL-5 + IL-13 → eosinophil recruitment/activation + alternative (M2) macrophage activation.
  • Th17 cells → IL-17 and other cytokines → chemokine production → mainly neutrophil recruitment.
• Th1 and Th17 cells help defend against many bacteria and viruses and also participate in chronic inflammation in diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
• Th2 cells are important in defense against helminth parasites and in allergic inflammation.
• Macrophages and T lymphocytes interact in a two-way feedback cycle.
• Macrophages → display antigen + express costimulators + produce cytokines such as IL-12 → activate T cells.
• Activated T cells → produce cytokines → recruit and activate more macrophages.
• More macrophage activation → more antigen presentation and cytokine release → chronic inflammation continues.
• Activated B lymphocytes and plasma cells are also commonly present in chronic inflammation.
• Plasma cells produce antibodies that may recognize persistent foreign antigens, self-antigens, or altered tissue components.
• However, the exact importance of these antibodies in many chronic inflammatory diseases remains unclear.
• In some chronic inflammatory conditions → lymphocytes + antigen-presenting cells + plasma cells organize into structures resembling lymph-node follicles.
• These structures are called tertiary lymphoid organs.
• They may occur in:
  • Long-standing rheumatoid arthritis
  • Hashimoto thyroiditis
  • Some cancers
• Their exact functional importance is not established.

Other Cells in Chronic Inflammation

• Other inflammatory cells may become prominent depending on the cause of chronic inflammation.
• Eosinophils are especially abundant in IgE-mediated immune reactions and parasitic infections (Fig. 2.18).
• Eosinophils are recruited by adhesion molecules and specific chemokines such as eotaxin.
• Their granules contain major basic protein → toxic to parasites but can also damage epithelial cells.
• Therefore, eosinophils are useful against parasites but also contribute to tissue injury in allergic reactions.
• Although neutrophils are typical of acute inflammation, they may also remain abundant in some forms of chronic inflammation.
• Persistent microbes or mediators from activated macrophages and T lymphocytes can continuously recruit neutrophils.
• In chronic osteomyelitis → neutrophil-rich exudate may persist for months.
• Neutrophils also contribute to chronic lung damage caused by smoking and other irritants.

KEY CONCEPT

• Macrophages → phagocytosis + inflammatory mediators + tissue repair + T-cell activation.
• Th1 → IFN-γ → M1 macrophages.
• Th2 → IL-4/IL-5/IL-13 → eosinophils + M2 macrophages.
• Th17 → IL-17 → neutrophil recruitment.
• Macrophage ↔ T-cell activation → self-amplifying cycle → persistent chronic inflammation.
• Eosinophils → parasites + allergy; neutrophils can also persist in chronic inflammation.

Conceptual Examples

• Persistent infection: Macrophage presents antigen → T cell activated → T cell activates more macrophages → chronic inflammation continues.
• Allergy: Th2 response → IL-4/IL-5/IL-13 → eosinophils increase → allergic inflammation and tissue damage.
• Chronic bacterial bone infection: Persistent microbes → continued neutrophil recruitment → neutrophilic inflammation persists for months.
• Rheumatoid arthritis: Persistent lymphocyte activation → macrophage–T-cell interaction continues → chronic inflammation is maintained.